OVERVIEW: Massachusetts Alzheimer?s Disease Research Center (MADRC) The MADRC is an interdisciplinary Center at Massachusetts General Hospital, Harvard Medical School, with two major strategic goals: 1) to understand the underpinnings of heterogeneity of Alzheimer?s disease and Alzheimer?s Disease Related Disorders, and 2) to develop techniques, strategies, and technologies to accelerate a cure. To approach these goals, we propose 7 Cores (Administrative, Clinical, Biomarker, Imaging, Neuropathology, Data, and Outreach). We will use advanced Imaging, Biomarker, and analytic approaches to study our Research Cohort, which we view as a state of the art clinical phenotyping laboratory. Autopsy follow up for validation of biomarkers and imaging, and therapeutic targets, is essential. We plan to study a diverse population, both in the sense of various pathophysiologies, and also with varying racial and ethnic backgrounds, and rely on a vigorous ORE core both to fulfill our own recruitment needs and to support clinical trials and other affiliated programs. We have refocused our Center?s activities by remodeling the Research Cohort to include subjects who are cognitively normal, have mild cognitive impairment, or dementia, targeting diverse causes of dementia including Alzheimer?s disease and related disorders (Frontotemporal dementia, Lewy Body Disease, and vascular lesions). We postulate that heterogeneity of progression, even among individuals with the same ?disease?, reflects underlying differences that can be uncovered, and that doing so will enhance clinical trial design by parsing variability from the very large, long cohort trials now in common use. Each Core is challenged to develop tools to help accelerate a cure ? from intermediate imaging/biomarker targets that may help with diagnosis (a patient?s state) or prognosis (a patient?s fate), to performing autopsies to validate those targets. We will develop markers of inflammation and neurodegeneration, believing that innate immunity and resilience play a role in addition to tangles and plaques. Development of statistical and data methods are critical for anlaysis. These tools will allow us to test hypotheses about faster or slower rates of progression in a deeply phenotyped cohort. A final goal, central to our mission, is to build the future by training the next generation of scientists, which we propose to do under the framework of the Research Education Component. Together, we hope to make a difference in these devastating diseases.